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INSULIN‐LIKE GROWTH FACTOR I (IGF‐1) REDUCES CHEMOKINES AND RECRUITMENT OF MONOCYTES INTO ATHEROSCLEROTIC PLAQUE: POTENTIAL MECHANISM MEDIATING IGF‐1‐INDUCED ATHEROPROTECTION
Author(s) -
Sukhanov Sergiy,
Snarski Patricia,
Higashi Yusuke,
Shai ShawYung,
Delafontaine Patrice
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.634.4
Subject(s) - chemokine , endocrinology , ccr2 , medicine , chemistry , chemokine receptor , macrophage , monocyte , receptor , cxcl1 , immunology , biochemistry , in vitro
We have shown that IGF‐1 decreased atherosclerosis and plaque macrophages in Apoe ‐/‐ mice. We hypothesized that IGF‐1 suppressed recruitment of circulating monocytes (MN) into plaque. Apoe ‐/‐ mice on a Western diet for 8 wks received IGF‐1 for 1 wk and red latex beads (2.5% wt/vol, i.v. specifically taken up by MN). IGF‐1 reduced Mac3 (macrophage marker)‐positive/red‐labeled cells in plaque (1.05±0.3, IGF‐1 vs.1.8±0.2 cells/plaque, control) without changes in labeled splenic MN. Similarly, chronic IGF‐1 (1.5 mg/kg/d, 4 wks) decreased labeled plaque MN (1.3±0.3, IGF‐1 vs. 2.6±0.4 cells/plaque, control). Conversely, mice with MN/macrophage‐specific IGF‐1 receptor deficiency (LCFIR) had increased labeled plaque MN (5.73±0.8, LCFIR vs. 2.33±0.4 cells/plaque, control). MN chemotaxis is mediated by chemokines/chemokine receptors. 6T/E mice with a 20% decline in circulating IGF‐I have increased atherosclerosis and chemokines in atherosclerotic aortas (RT array, MCP‐1, 185%; CCR1, 118%; CCR2, 99% increase vs. WT) and increased levels of circulating chemokines (ELISA, MCP‐1, 19.7 vs. 7.6 pg/ml; CXCL1, 74.4 vs. 24.9 pg/ml; E‐selectin, 70.1 vs. 48.9 pg/ml, 6T/E vs. WT). We quantified IGF‐1 effects on chemokines and on MN adhesion using human THP‐1 MN. IGF‐1 (50 ng/ml, 24h) decreased MCP‐1 (43±6% decrease), CCR1 (40±4% decrease) and CCR2 (38±5% decrease) mRNA in THP‐1 and suppressed adhesion of calcein‐labeled MN to endothelial cells (22±4% decrease). Taken together, these data suggest that IGF‐1 downregulation of chemokines reduces MN recruitment into atherosclerotic plaque mediating IGF‐1's anti‐atherosclerotic effect.